Caelyx concentrate 2mg/ml 10ml vial, 1pc

Composition

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1 ml (1 bottle) contains:

Active ingredients: pegylated liposomal doxorubicin hydrochloride 2 mg (20 mg).

Excipients: sodium carbamoyl methoxypolyethylene glycoldistearoylglycerophosphoethanolamine, phosphatidylcholine, cholesterol (cholesterol), ammonium sulfate, sucrose, histidine, hydrochloric acid, sodium hydroxide, water for injection.

In a bottle of 10 ml. In a cardboard box 1 bottle.

Pharmacological action

Pharmacodynamics

Antitumor drug. Doxorubicin is a cytotoxic anthracycline antibiotic isolated from Streptomyces peucetius var. caesius. The exact mechanism of antitumor action of doxorubicin is unknown. It is believed that the cytotoxic effect is due to its ability to inhibit the synthesis of DNA, RNA and proteins by introducing doxorubicin between adjacent base pairs of the DNA double helix, which prevents the helix from unfolding for subsequent replication.

Kelix® is a pegylated liposomal form of doxorubicin that circulates in the blood for a long time and provides a higher concentration of doxorubicin in tumor tissue than in normal tissues. Liposomes contain surface-bound hydrophilic polymers of methoxypolyethylene glycol (MPEGs). Linear groups of MPEGs create a protective shell protruding above the liposome surface, reducing the possibility of interaction between the lipid bilayer membrane and plasma components, which protects liposomes from recognition by the phagocytic system and allows you to extend the circulation time of doxorubicin in the bloodstream. Pegylated liposomes also have a lipid matrix with low permeability and an internal water buffer system, which in combination allows you to keep doxorubicin inside the liposome during its circulation in the bloodstream. The relatively small size of pegylated liposomes (an average diameter of approximately 100 nm) allows them to penetrate through defects in the blood vessels of the tumor. The results of experimental studies indicate the penetration of pegylated liposomes from blood vessels and their accumulation in tumors.

Pharmacokinetics

Distribution and breeding

When administered intravenously with Kelix®, the plasma doxorubicin concentration and AUC are predominantly pegylated liposomal doxorubicin (90% to 95% of the measured doxorubicin, respectively), and are significantly higher than when administered with equivalent doses of traditional (non-pegylated non-liposomal) doxorubicin. The pharmacokinetic profile of doxorubicin indicates that its plasma clearance is determined by the liposomal carrier. Doxorubicin becomes available only after liposomes leave the vascular bed and enter the tissues.

In low doses (10-20 mg/m2), the linear pharmacokinetics of Caelyx is shown, in higher doses (20-60 mg/m2) – nonlinear.

When the drug is administered at a dose of 10 to 60 mg/m 2 doxorubicin clearance is an average of 0.03 l/h/m 2 (0,008-of 0.152 l/HR/m 2), V_d is 1.93 l/m2 (0,96-3,85 l/m 2), T_1/2 – 73,9 h (24-231 hrs).

Pharmacokinetics in special clinical cases

, the pharmacokinetic parameters of impaired liver function and hyperbilirubinemia differ slightly from the pharmacokinetic parameters of normal total bilirubin concentration.

Renal insufficiency (creatinine clearance 30-156 ml / min) does not affect the pharmacokinetic parameters. There are no data on the pharmacokinetics of the drug in patients with creatinine clearance less than 30 ml/min.

The age of patients (21-75 years) does not significantly affect the pharmacokinetic parameters of the drug Kelix®.

Indications

• Metastatic breast cancer in the presence of indications for therapy with anthracyclines, including in the case of increased risk of cardiac complications and failure of therapy takanami;
• common ovarian cancer after failure of chemotherapy with platinum drugs;
• progressive multiple myeloma (in combination with bortezomib) in patients who received at least one line of chemotherapy and had undergone bone marrow transplantation (BMT), or who are not candidates for bone marrow transplantation.

Use during pregnancy and lactation

The drug is contraindicated for use during pregnancy and lactation.

Men and women of childbearing age should use reliable methods of contraception during treatment, as well as for 6 months after its cancellation.

Contraindications

• Age up to 18 years;
• pregnancy;
• lactation (breastfeeding);
• hypersensitivity to the components of the drug.

With caution: the drug should be used for circulatory insufficiency, previous use of other anthracyclines, co-use with drugs with cytotoxic (especially myelotoxic) effects, gout (including in the anamnesis), urate nephrourolithiasis (including in the anamnesis), heart disease (cardiotoxic effect can be observed at lower total doses), liver failure.

Inhibition of bone marrow hematopoiesis (including infiltration of the bone marrow with tumor cells, previous chemotherapy or radiation therapy), parasitic and infectious diseases of a viral, fungal or bacterial nature (currently or recently transferred, including recent contact with the patient: herpes simplex, herpes zoster /viremic phase/, chickenpox, measles, amoebiasis, strongyloidosis /established or suspected/) increase the risk of developing severe generalized disease.

Side effects

Determining the frequency of side effects:

• common (≥5%);
• infrequent (1% to < 5%);
• rare (

Severe adverse reactions (serious and life-threatening) account for 0 to 5% of the number of adverse events of each type, and only in some cases their frequency is higher (in leukopenia-6.8%, stomatitis-7.4%, neutropenia-8.5%, palmar-plantar syndrome-19%).

From the hematopoietic system: myelosuppression (anemia, thrombocytopenia, leukopenia, neutropenia); rarely-neutropenic fever. Patients with ovarian cancer often have hematological toxicity. Breast cancer patients often have anemia; infrequently, leukopenia, neutropenia, and thrombocytopenia. In patients with multiple myeloma (treated with Kelix® in combination with bortezomib), lymphopenia and neutropenic fever are uncommon.

From the cardiovascular system: infrequently-chest pain, peripheral edema, tachycardia, hot flashes, cardiotoxic effect (clinically significant change in the left ventricular ejection fraction, in rare cases associated with symptoms of congestive heart failure); rarely – lowering blood pressure. In patients with multiple myeloma infrequently – lowering or increasing blood pressure, orthostatic hypotension, phlebitis. The frequency and severity of cardiotoxicity symptoms with Caelyx therapy is lower than with traditional doxorubicin therapy at comparable doses.

From the digestive system: often-abdominal pain, anorexia, constipation, diarrhea, mucositis, stomatitis, nausea, vomiting; infrequently – dehydration, dry mouth, dyspepsia, dysphagia, esophagitis, gastritis, gingivitis, ulceration of the oral mucosa, taste distortion; rarely – flatulence, pain in the oral cavity. Patients with multiple myeloma often have dyspepsia, aphthous stomatitis and decreased appetite, taste distortion; infrequently, upper abdominal pain.

Dermatological reactions: often – palmar-plantar syndrome (erythrodysesthesia), alopecia, skin rash, erythema; infrequently – dry skin, dermatitis, exfoliative dermatitis, macular-papular rash, vesiculobullous rash, nail damage, skin pigmentation disorders, skin ulcers, itching of the skin; rarely-acne, bullous rash, desquamation of the epidermis, urticaria; very rarely – erythema multiforme, Stevens – Johnson syndrome, toxic epidermal necrolysis. Patients with multiple myeloma often have dry skin; infrequently, alopecia, allergic dermatitis, drug-induced dermatitis, erythema, papular rash, petechiae, and pruritus.

From the nervous system: often-paresthesia, fatigue; infrequently-dizziness, drowsiness, anxiety; rarely-neuropathy, depression, increased smooth muscle tone. Patients with multiple myeloma often have headache, dizziness, insomnia, neuralgia, neuropathy, peripheral neuropathy, peripheral sensory neuropathy, and polyneuropathy; infrequently, syncope, dysesthesia, hypesthesia, and drowsiness.

From the musculoskeletal system: infrequently-myalgia; rarely-ossalgia. Patients with multiple myeloma often have pain in the extremities, rarely-arthralgia, muscle weakness, muscle spasms and chest pain.

From the side of the organ of vision: infrequently-conjunctivitis; rarely-lacrimation.

From the side of the reproductive system and mammary glands: infrequently-erythema of the scrotum.

Infusion reactions: (mainly observed during the first infusion and as a result of interactions with other medications) anaphylactoid reactions, choking attack, facial edema, vasodilation, increased or decreased blood pressure, urticaria, back pain, chest pain, chills, fever, tachycardia, dyspepsia, nausea, dizziness, difficulty breathing, pharyngitis, skin rash, itchy skin, increased sweating, convulsions (very rare) as well as injection site reactions. In patients with multiple myeloma treated with Kelix® and bortezomib, the rate of infusion reactions was 3%. Temporary suspension of the infusion usually leads to the relief of these reactions without additional treatment. With subsequent injections of Kelix, infusion reactions rarely resume.

Local reactions: if the drug gets under the skin, rarely – necrosis of the surrounding tissues.

Clinically significant changes in laboratory data: infrequently-increased activity of ACT and total bilirubin in the blood serum, increased concentration of serum creatinine; rarely-increased activity of ALT in the blood serum. In patients with multiple myeloma infrequently – increased ALT activity in the blood serum, hyperkalemia, hypocalcemia, hypokalemia, hypomagnesemia, hyponatremia.

Other: often – asthenia, fever, pharyngitis, fatigue, weakness; infrequently – headache, malaise, increased cough, shingles, candidiasis of the oral mucosa, increased sweating, urinary tract infection, thrombophlebitis, venous thrombosis; rarely – anaphylactic reactions, cachexia, folliculitis, herpes simplex, sepsis, upper respiratory tract infection, pulmonary embolism arteries, dysuria, vaginitis, genital candidiasis. Patients with multiple myeloma often have shortness of breath, herpes simplex, shingles, weight loss, chills, pneumonia, upper respiratory tract infections, nasopharyngitis, fever, viral infections, peripheral edema, nosebleeds, and shortness of breath during exercise.

Combination therapy

From the hematopoietic system: neutropenia, thrombocytopenia and anemia are most common in patients receiving both combination therapy with Kelix® and bortezomib, and monotherapy with bortezomib. The incidence of grade 3-4 neutropenia with combination therapy was higher than with bortezomib monotherapy (28% and 14%, respectively). The incidence of grade 3-4 thrombocytopenia was also higher in patients receiving combination therapy (22% and 14%, respectively). The incidence of anemia was comparable in the two groups (7% and 5%).

From the digestive system: with combination therapy, stomatitis was more common (16%) than with monotherapy (3%). Most cases of stomatitis were < 2 degrees of severity. Grade 3 stomatitis developed in 2% of patients receiving combination therapy. No cases of grade 4 stomatitis were registered. Nausea and vomiting were more common in patients receiving combination therapy (40% and 28%, respectively) than in patients receiving monotherapy (32% and 15%). Most cases were 1-2 degrees of severity.

Treatment with bortezomib or a combination of drugs (bortezomib and Kelix®) was discontinued due to adverse events in 38% of patients. Palmar-plantar syndrome, neuralgia, peripheral neuropathy, thrombocytopenia, decreased left ventricular ejection fraction, and fatigue were the main adverse reactions that led to discontinuation of bortezomib or Kelix®.

Interaction

When co-administered with cyclophosphamide or taxanes in patients with solid tumors (including ovarian and breast cancer), no increase in toxicity was detected. However, it should be borne in mind that Kelix®, like other doxorubicin hydrochloride preparations, may increase the toxic effect of other antitumor drugs.

Hepatotoxic drugs, which impair liver function, can lead to increased toxicity of doxorubicin.

When administered concomitantly with live viral vaccines, it is possible to intensify the process of replication of the vaccine virus, increase its side/adverse effects and / or reduce the production of antibodies in the patient’s body in response to the introduction of the vaccine, so the interval between discontinuation of the drug and vaccination varies from 3 months to 1 year.

Pharmaceutical interaction

Kelix® should not be mixed with solutions other than 5% dextrose solution for infusion.

The presence of bacteriostatic additives, such as benzyl alcohol, in the infusion solution can cause precipitation of Kelix.

How to take, course of use and dosage

The drug is administered intravenously. The drug should not be administered in a jet or undiluted form.

Treatment is continued until signs of progression or unacceptable toxicity develop.

In breast cancer and ovarian cancer, the drug is administered at a dose of 50 mg / m2 1 time in 4 weeks.

In the treatment of multiple myeloma, Kelix® is administered at a dose of 30 mg / m2 on the 4th day of a three-week cycle in combination with bortezomib (1.3 mg/m2 on days 1,4,8 and 11). Caelyx is administered immediately after bortezomib. If it is not possible to administer Kelix® and bortezomib on day 4 of the cycle, their use can be postponed for 48 hours. If bortezomib was administered later than the time indicated in the treatment schedule, then the subsequent use of bortezomib should be carried out no earlier than 72 hours after the last dose.

At a calculated dose of less than 90 mg, the concentrate is diluted in 250 ml of 5% dextrose solution for infusion; at a dose of 90 mg or more-in 500 ml.

The first use is carried out at a rate of no more than 1 mg/min in order to reduce the risk of developing infusion reactions. In the absence of reactions, subsequent infusions can be performed within 60 minutes.

use of the drug to patients who have experienced infusion reactions to previous use should be modified as follows: 5% of the calculated dose is administered slowly for 15 minutes. In the absence of reactions, the use is continued at twice the rate for another 15 minutes. If well tolerated, the infusion is continued for the next hour (the total time of use is 90 minutes).

The intravenous catheter and dropper should be flushed with a 5% dextrose solution between the use of bortezomib and Kelix.

Modification of the dosage regimen

Instructions for changing the dosage regimen of Kelix® are given in Tables 1-4.

The toxicity levels shown in the tables are based on the National Cancer Institute Toxicity Scale (NCI-CTC).

Table 1. Modification of the dosage regimen due to the development of palmar-plantar syndrome

Table 2. Modification of the dosage regimen due to the development of stomatitis

Table 3. Dosage regimen modifications due to the development of hematological toxicity

Table 4. Modification of the dosage regimen for multiple myeloma

* – for more information, see the instructions for use of bortezomib.

If a patient with multiple myeloma receiving combination therapy with Kelix® and bortezomib develops palmar-plantar syndrome or stomatitis, then the dose of Kelix® should be adjusted as indicated in tables 1 and 2.

In patients with impaired liver function with a bilirubin content in the blood serum from 1.2 to 3 mg/dl, the calculated dose is reduced by 25%. If the bilirubin content exceeds 3 mg / dl, the calculated dose is reduced by 50%. If the patient tolerates this dose well (without hyperbilirubinemia or increased activity of liver enzymes in the blood serum), then the next dose is increased to the previous level (i. e., if the dose is reduced by 25%, it is increased to the full dose, if the dose is reduced by 50%, it is increased to 75% of the full dose). If well tolerated in subsequent cycles, the dose can be increased to the full dose. Kelix® can be prescribed to patients with liver metastases with concomitant hyperbilirubinemia and increased activity of liver enzymes up to 4 times the ULN. Before the introduction of Kelix, a clinical and laboratory study of liver function should be performed, including the determination of the activity of ALT, AST, alkaline phosphatase, and bilirubin.

Patients with impaired renal function do not need to adjust the dosage regimen.

Overdose

Symptoms: severe myelosuppression (mainly leukopenia and thrombocytopenia), toxic effects from the gastrointestinal tract (mucositis).

Treatment: in case of acute overdose in patients with severe myelosuppression, treatment should be carried out in a hospital and include the use of antibiotics, transfusion of granulocytes and platelets, and symptomatic therapy of mucositis.

Special instructions

Kelix® should be used under the supervision of a physician experienced in cytostatic therapy.

Since Kelix® has special pharmacokinetic properties, alternating cycles of therapy with Caelyx and traditional doxorubicin should not be performed.

An increase in the incidence of congestive heart failure is possible with a total dose of doxorubicin exceeding 450 mg / m2, or at a lower dose – in the presence of risk factors from the cardiovascular system (previous radiotherapy for the mediastinal region or therapy in combination with cyclophosphamide).

ECG monitoring is recommended for all patients receiving Caelyx therapy. Transient changes on the ECG, such as flattening of the T wave, reduction of the ST segment, and clinically insignificant rhythm disturbances are not mandatory indications for discontinuation of Kelix. A specific manifestation of the cardiotoxic effect is a decrease in the voltage of the QRS complex. If such a change occurs, a myocardial biopsy should be considered as the most specific test for diagnosing heart muscle damage caused by anthracyclines.

Methods for measuring the left ventricular ejection fraction-echocardiography and the preferred MUGA scan (multi – input arteriography) – are more specific methods for monitoring the state of heart function compared to ECG. These methods should be used before and during Caelyx therapy. Measurement of the left ventricular ejection fraction is mandatory for each subsequent use of Caelyx with a total dose of the drug exceeding 450 mg / m2.

If cardiomyopathy is suspected, i. e. if the left ventricular ejection fraction is lower than this indicator before starting treatment and/or if there is a prognostically significant decrease in this indicator (less than 45%), a myocardial biopsy should be performed.

The listed research methods to identify the possible negative effects of anthracycline therapy on cardiac activity are recommended to be used in the following sequence: ECG monitoring, measurement of the left ventricular ejection fraction, and myocardial biopsy.

If the results of the examination suggest myocardial damage associated with Caelyx therapy, a careful assessment should be made of the ratio of the expected benefit from continuing to use Caelyx and the risk of developing cardiotoxicity.

Congestive heart failure due to cardiomyopathy may develop unexpectedly, without previous changes in the ECG, and may also appear several weeks after discontinuation of therapy.

Patients with cardiological diseases that require appropriate therapy, the appointment of Caelyx is possible only if the benefit of the drug outweighs the risk to the patient.

When calculating the cumulative dose of doxorubicin, any previous or concomitant use of cardiotoxic drugs (other anthracyclines/anthraquinones or 5-fluorouracil) should be taken into account.

During therapy with Kelix, the picture of peripheral blood should be monitored regularly and, at least, before each use of the drug, with mandatory counting of the number of cells.

Persistent severe myelosuppression can lead to superinfection or bleeding.

Secondary acute myeloblastic leukemia and myelodysplastic syndrome have been reported in patients receiving combined chemotherapy including doxorubicin (as with other DNA-binding antitumor drugs), and therefore it is recommended that such patients periodically monitor their hematological parameters.

Infusion reactions usually occur during the first infusion. Temporary suspension of the infusion usually leads to resolution of symptoms without additional treatment. However, when Caelyx is administered, medications designed to stop infusion reactions (epinephrine, antihistamines, corticosteroids, and other medications for emergency medical care) should be prepared.

If symptoms of an infusion reaction occur, the infusion should be stopped immediately and symptomatic therapy (including antihistamines and/or short-acting corticosteroids) should be performed. Resumption of infusions is possible after complete relief of all symptoms with a decrease in the rate of use of Kelix. Infusion reactions rarely recur after the first cycle of Caelyx therapy.

Palmar-plantar syndrome usually appears after 2-3 cycles of therapy. In most patients, symptoms resolve after 1-2 weeks (with or without corticosteroids).

For the prevention and treatment of this syndrome, pyridoxine is used at a dose of 50-150 mg / day. Other methods of treatment and prevention of palmar-plantar syndrome begin 4-7 days after the introduction of Kelix.To prevent this syndrome, you should keep your hands and feet in a cool state (hand and foot baths and body baths with low water temperature, swimming in cool water); you should also avoid excessive exposure to warm/hot water and try not to wear tight-fitting socks, gloves, tight shoes, so as not to disrupt blood circulation in the legs and hands.

The manifestations of this complication can be significantly reduced by increasing the interval between injections for 1-2 weeks or by reducing the dose. However, these reactions may be severe and require discontinuation of therapy.

If symptoms of extravasal ingestion of the drug (burning, redness) appear, immediately stop the infusion and cover the injection site with ice for 30 minutes. use of the drug is continued to another vein.

When prescribing the drug to patients with diabetes mellitus, it should be taken into account that Kelix® contains sucrose, and that the drug is administered together with a 5% dextrose solution.

Use in pediatrics

The safety and efficacy of Caelyx in patients under 18 years of age are not fully understood.

Influence on the ability to drive vehicles and other mechanisms that require increased concentration of attention

Although Kelix® does not directly affect the ability to drive a car, however, some patients may experience dizziness, drowsiness. Therefore, during the treatment period, it is necessary to refrain from driving a car and operating mechanisms.

Form of production

Concentrate for preparing a solution for intravenous use.

Storage conditions

At a temperature of 2-8 °C (do not freeze)

Shelf

life 20 months

Active ingredient

Doxorubicin

Conditions of release from pharmacies

By prescription

Dosage form

infusion solution